A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA.
A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA.
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DOI：
10.1042/bj20100668
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发表时间：
2010-11-01
期刊：
影响因子：
--
通讯作者：
Muckenthaler MU
中科院分区：
文献类型：
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作者：
Altamura S;D'Alessio F;Selle B;Muckenthaler MU
IRIDA（铁难治性缺铁性贫血）是一种罕见的常染色体隐性遗传疾病，其特征是低色素性小细胞贫血，低转铁蛋白饱和度和高水平的铁调节激素铁调素。该疾病是由跨膜丝氨酸蛋白酶TMPRSS6（跨膜丝氨酸蛋白酶6）中的突变引起的，该突变阻止了HJV（血幼素）的失活，HJV是铁调素转录的激活剂。在本文中，我们描述了一个病人IRIDA谁携带一个新的突变（Y141C）在SEA域的TMPRSS6基因。培养细胞中TMPRSS6（Y141C）突变蛋白的功能表征表明，其定位于与野生型TMPRSS6相似的亚细胞区室并结合HJV，但不能自催化激活自身。因此，铁调素mRNA表达增加，导致在该IRIDA患者中观察到的临床症状。本研究为TMPRSS6如何被激活提供了重要的机制见解。
IRIDA (iron-refractory iron-deficiency anaemia) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anaemia, low transferrin saturation and high levels of the iron-regulated hormone hepcidin. The disease is caused by mutations in the transmembrane serine protease TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of HJV (haemojuvelin), an activator of hepcidin transcription. In the present paper, we describe a patient with IRIDA who carries a novel mutation (Y141C) in the SEA domain of the TMPRSS6 gene. Functional characterization of the TMPRSS6(Y141C) mutant protein in cultured cells showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. As a consequence, hepcidin mRNA expression is increased, causing the clinical symptoms observed in this IRIDA patient. The present study provides important mechanistic insight into how TMPRSS6 is activated.